The aim of this project, like that of the overall proposal, is to test the value of studying abnormalities in extraneural tissues from Alzheimer (DAT) patients by testing the relation of these abnormalities to the clinical syndrome or its subgroups. Clinically, DAT patients, patients with other disorders (disease controls), and spousal and other unrelated cognitively intact subjects of comparable age and sex (intact controls) will be extensively examined through an established clinical dementia service. All, including intact controls, will receive neuropsychological testing. All will, if possible, be followed up to autopsy. Cultures of cells from skin will be meticulously controlled, including biopsy site and parameters related to biological age in culture (cumulative population doubling level [cPDL] and % life-span completed), to ensure that DAT and control cells are studied under comparable conditions. Parameters measured in the cells will include two related to materials which accumulate in DAT brain. The amyloid precursor protein (APP) will be studied at both the mRNA and protein (immunochemical) levels. Materials which react with antibodies to paired helical filaments (PHF) will be studied immunocytochemically, using semiquantitative techniques, and culture conditions which the PI and coworkers have found lead to expression of anti-PHF reactive materials in cultured DAT cells and to a much lesser degree in cells from controls. (Project 2 aims to develop quantitative immunochemical techniques to measure anti-P HF reactive materials, which would then be applied to these cells.) Other parameters measured in the cultured cells will be those found by at least two laboratories (including this unit) to be abnormal in cultured DAT cells: isoproterenol-stimulated cyclic AMP synthesis, cellular calcium homeostasis, and oxidation of [U-14C]glutamine. Data will be stored in a relational data base (SIR software), and the relations of the abnormalities in the cultured cells to the clinical syndrome of DAT or its subtypes tested by detailed statistical analysis with a statistical consultant. In future studies, the diagnostic utility of any abnormalities in the cultured cells which are found to relate to the disease will be tested, including whether they appear to be trait- or state-dependent markers.